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Gheorghiade M.,Northwestern University | Larson C.J.,Cardiovascular and Metabolic Diseases Drug Discovery Unit | Shah S.J.,Northwestern University | Greene S.J.,Duke University | And 19 more authors.
Circulation: Heart Failure | Year: 2016

Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeaway dialogue from this meeting. © 2016 American Heart Association, Inc.

Handberg A.,Aarhus University Hospital | Norberg M.,Umea University | Stenlund H.,Umea University | Hallmans G.,Umea University | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context and Objective: Soluble CD36 (sCD36) may be an early marker of insulin resistance and atherosclerosis. The objective of this prospective study was to evaluate sCD36 as a predictor of type 2 diabetes and to study its relationship with components of the metabolic syndrome (MetSy). Design, Setting, Participants, and Outcome Measures: We conducted a case-referent study nested within a population-based health survey. Baseline variables included sCD36, body mass index, blood pressure, blood lipids, adipokines, inflammatory markers, and β-cell function. A total of 173 initially nondiabetic cohort members who developed type 2 diabetes during 10 yr of follow-up were matched (1:2) with referents. Exploratory factor analysis was applied to hypothesize affiliation of sCD36 to the MetSy components. Results: Doubling of baseline sCD36 increases the odds ratio for diabetes development by 1.24 in the general study population and by 1.45 in the female population (P < 0.025). Comparing upper sCD36 quartiles with lower, odds ratio for diabetes was 4.6 in women (P=0.001), 3.15 in men (P= 0.011), and 2.6 in obese individuals (P < 0.025). Multivariate analysis shows that sCD36 does not predict diabetes independent of fasting plasma glucose and insulin. Factor analysis of 15 variables generates a six-factor model explaining 66-69% of total variance, where sCD36, body mass index, insulin, proinsulin, and leptin were assigned to the obesity/insulin resistance cluster. Conclusions: Upper quartile sCD36 is associated with elevated diabetes risk independent of age, gender, and obesity. Baseline sCD36 does not, however, predict diabetes independent of fasting glucose and insulin. sCD36 clusters with important markers of insulin resistance and MetSy that are key predictors of type 2 diabetes. Copyright © 2010 by The Endocrine Society.

Bui A.H.,Harvard University | Cannon C.P.,Harvard University | Steg P.G.,French Institute of Health and Medical Research | Steg P.G.,Departement Hospitalo University | And 13 more authors.
Circulation: Arrhythmia and Electrophysiology | Year: 2016

Background-Nonsustained ventricular tachycardia (NSVT) is common after acute coronary syndrome (ACS) and a marker of increased risk of arrhythmogenic death. However, the prognostic significance of NSVT when evaluated with other contemporary risk markers and at later time points after ACS remains uncertain. Methods and Results-In the Platelet Inhibition and Patient Outcomes (PLATO) trial, continuous ECGs were performed during the first 7 days after ACS (n=2866) and repeated for another 7 days at day 30 (n=1991). Median follow-up was 1 year. There was a time-varying interaction between NSVT and cardiovascular death such that NSVT was significantly associated with increased risk within the first 30 days after randomization (22/999 [2.2%] versus 16/1825 [0.9%]; adjusted hazard ratio, 2.84; 95% confidence interval, 1.39-5.79; P=0.004) but not after 30 days (28/929 [3.0%] versus 42/1734 [2.4%]; P=0.71). Detection of NSVT during the convalescent phase (n=428/1991; 21.5%) was also associated with an increased risk of cardiovascular death, and was most marked within the first 2 months after detection (1.9% versus 0.3%; adjusted hazard ratio, 5.48; 95% confidence interval, 1.07-28.20; P=0.01), and then decreasing over time such that the relationship was no longer significant by ≈5 months after ACS. Conclusions-NSVT occurred frequently during the acute and convalescent phases of ACS. The risk of cardiovascular death associated with NSVT was the greatest during the first 30 days after presentation; however, patients with NSVT detected during the convalescent phase were also at a significantly increased risk of cardiovascular death that persisted for an additional several months after the index event. © 2016 American Heart Association, Inc.

Johnson D.M.,Maastricht University | De Jong M.M.J.,Maastricht University | Crijns H.J.G.M.,Maastricht University | Carlsson L.G.,Astra Zeneca Research and Development | Volders P.G.A.,Maastricht University
Circulation: Arrhythmia and Electrophysiology | Year: 2012

Background-AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling. Methods and Results-AZD1305 was administered to anesthetized mongrel dogs before and >2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective IKr blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison. At normal sinus rhythm, AZD1305 increased QT and RR intervals from 290 ± 7 to 397 ± 15 ms (≈37%, P <0.0001) and from 603 ± 22 to 778 ± 32 ms (≈29%, p <0.002), respectively. In the same animals at chronic atrioventricular block, AZD1305 increased the QT interval from 535 ± 28 to 747 ± 36 ms (≈40%, P <0.0001), similar to the QT prolongation by dofetilide (511 ±22 to 703 ± 45 ms [≈38%, P <0.0001]). AZD1305 slightly slowed the idioventricular rhythm. Whereas all (n=14) chronic atrioventricular block animals exhibited torsades de pointes on dofetilide, the arrhythmia was induced in only 4 of 11 dogs after AZD1305. Beat-to-beat variability of left-ventricular monophasic-action-potential duration increased after dofetilide (2.3 ±0.2 to 6.3 ± 0.7 ms; P <0.0001) but not after AZD1305 (2.8 ± 0.3 to 3.7 ± 0.3 ms; p <0.20) despite similar left-ventricular monophasic-action-potential duration prolongations. Conclusions-Despite causing similar degrees of repolarization delay as the selective IKr blocker dofetilide, the combined ion-channel blocker AZD1305 induces less repolarization instability and has a lower ventricular proarrhythmic potential in the remodeled dog heart. © 2011 American Heart Association, Inc.

Redfors B.,Gothenburg University | Redfors B.,Sahlgrenska University Hospital | Shao Y.,Gothenburg University | Wikstrom J.,Astra Zeneca Research and Development | And 5 more authors.
European Heart Journal Cardiovascular Imaging | Year: 2014

Aims Stress-induced cardiomyopathy (SIC) is an important differential diagnosis to acute myocardial infarction (AMI) that is associated with significant morbidity and mortality. The typical hallmark of SIC is left-ventricular apical akinesia but preserved function in basal segments. Catecholamines are postulated to play an important role in SIC but the precise pathophysiology is incompletely understood. Whether myocardial perfusion of the affected segments is impaired in SIC has been debated and remains unknown. Methods and results Myocardial contrast echocardiography (MCE) was used to study regional myocardial perfusion in a rat model of SIC. Twelve rats received 50 mg/kg isoproterenol (ISO) i.p. and were continuously monitored by MCE. Apical and basal perfusion were estimated and expressed as a ratio at baseline, 5, 10, 20, 30, 40, 50, 60, 70, 80, and 90 min post-ISO. The rats developed typical apical ballooning after 43 ± 9 min post-ISO injection. The ratio of apical:basal perfusion was close to 1.00 at all time-points and never dropped below 0.89 (95% CI never extended below 0.73). Light and electron microcoscopical investigation revealed no structural damage of myocardial vessels. Conclusion Apical perfusion is not impaired in the early phase of SIC in this rat model. All rights reserved. © The Author 2013.

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